PROJECT SUMMARY Our long-term research goal is to understand the mechanisms underlying postoperative cognitive dysfunction (POCD) and postoperative dementia in older adults in order to ultimately prevent this complication. The overall objective of this application is to determine whether known AD risk factors represent risk factors for POCD. Realization of these goals will enable researchers to move toward developing novel preventive or therapeutic strategies, and will allow clinicians to provide accurate informed consent, appropriate counseling to caregivers, and deliver the safest perioperative care tailored to the individual geriatric patient. Neurocognitive dysfunction is one of the most common postoperative complications experienced by individuals aged 65 years and older, and these older adults comprise more than 1/3 of the surgical patients in the United States each year. For decades, patients and their families have reported lasting postoperative cognitive changes. However, not everyone with a history of surgery and anesthesia develops postoperative cognitive dysfunction (POCD), suggesting biological risk factors are involved. There are important gaps in our knowledge regarding who is at risk for developing POCD. Based on our preliminary data obtained from an analysis of longitudinal aging studies, our central hypothesis is that both biological sex and presence of specific genetic polymorphisms place older adults at higher risk for accelerated cognitive decline following exposure to surgery and anesthesia. While retrospective studies are limited in terms of details regarding surgery and anesthesia, and are based on self-report of exposures, a prospective study is necessary to more definitively evaluate the hypotheses generated to date with appropriate annotation of and adjustment for perioperative factors. The premise of the proposed research is that once specific risk factors for postoperative cognitive dysfunction are identified, at-risk individuals can be targeted for future clinical studies to reduce risk of POCD. We plan to test our central hypothesis with a prospective cohort study of men and women at least 65 years old who undergo elective spine surgery under general anesthesia. We will pursue these specific aims: Aim 1: Determine whether polymorphisms in APOE, PLA, PDE4D, or COMT increase the risk of postoperative cognitive decline in older adults Aim 2: Determine the interaction between biological sex and genotype on postoperative decline in cognition and functional status in older adults.